Chronic Liver Disease

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Station 1: Abdominal Exam

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Chronic Liver DiseaseDefinition
Chronic liver disease is a process whereby there is progressive disease and destruction to the liver resulting in fibrosis and eventually cirrhosis.


Signs
General signs include: Cachexia, bruising, pallor, and excoriations
Hands signs: leuconychia, finger clubbing, dupuytrens contracture, palmar erythema and asterixis
Chest/abdo signs: – spider naevi (4 or more is pathological), distended abdominal veins and/or caput medusa, decreased body hair, gynaecomastia, testicular atrophy, ascites
Hepatic signs – there may be a mass in the RUQ which moves with respiration, which you are unable to get above and is dull to percussion. If hepatomegaly is present estimate its size in cm below the costal margin and describe its consistency for example craggy/nodular hepatomegaly may represent cirrhosis, smooth may represent hepatic congestion, or pulsatile suggests tricuspid regurgitation in CCF
Signs of underlying cause of CLD: Tattoos and injection marks may suggest viral hepatitis, obesity suggesting non-alcoholic fatty liver disease, tremor suggesting alcoholic liver disease
Lastly, comment on whether the liver disease is compensated or decompensated: the presence of jaundice, ascites or encephalopathy suggest decompensated liver disease
To complete: mention that you would want to perform a PR examination and examine the external genitalia


Symptoms include:
Fatigue and drowsiness which may suggest encephalopathy
Nausea and vomiting
Abdominal pain
Development of ascites or oedema – the patient may initially perceive this as weight gain
Jaundice
Pruritus


Causes
The 3 most common causes of CLD in UK are:


Alcohol
Viral hepatitis
Non-alcoholic fatty liver disease – therefore comment on the patient’s BMI


Other causes:
Autoimmune causes such as autoimmune hepatitis and primary biliary cirrhosis (PBC). Both of these are much more common in female patients – PBC occurs most commonly in middle aged women and autoimmune hepatitis, particularly affects those aged between 15 and 40 but it can occur in any age group. Therefore always include these in the differential if the patient is female in a CLD station
Metabolic causes e.g. hereditary haemochromatosis and Wilsons disease – look for skin pigmentation associated with haemochromatosis, and Kaiser Fleischer rings in the eyes which are seen in Wilsons disease
Drugs e.g. methotrexate and amiodarone  – signs of rheumatological disease or is a pacemaker present
Some causes of chronic liver disease are idiopathic
 
Investigations
A Full liver screen should be sent including:
FBC/U+E/LFT/clotting/CRP/glucose/Gamma GT
Hep B/Hep C/EBV/CMV serologies
Ferritin
Autoantibody screen including (ANA, antmitochondrial, antiLKM antibodies, anti-smoothmuscle antibodies)
Serum caeruloplasmin/copper/24 hour urinary copper
Alpha-1 antitrypsin
Alpha Fetoprotein
USS abdo
Ascitic tap if ascites present and diagnosis unclear
Liver biopsy
MRCP/ERCP


Management
Management of Chronic Liver Disease includes:
Alcohol abstinence
Replacement of vitamins and thiamine
Optimise nutrition
Salt restriction
Diuretics if oedema or ascites present- start with spironolactone and then add in loop diuretics if further diuresis is still required – aim to achieve approximately 1kg of weight loss/day, with careful monitoring of renal function and electrolytes.
Prophylactic agents may be necessary such as propranolol if varices are present
Regular laxatives to avoid encephalopathy (aim for 3 soft stools/day)
Avoid hepatotoxic medications
Further management considerations may include a TIPS procedure or a liver transplant


A TIPS procedure is a transjugular intrahepatic portal shunt. A shunt is inserted directing blood from the hepatic portal vein to the hepatic vein, reducing pressure over the liver and alleviating portal hypertension. They are inserted by interventional radiologists.




Top tip
When faced with a patient with chronic liver disease try to establish the cause if possible. For example in a middle aged lady suggest PBC as differential. Also specify whether the liver disease is compensated or decompensated. Most likely the disease will be stable and compensated for patients used in the exam but sometimes you can be caught out.


Chronic liver disease is a common station and the examiners can ask many related questions once you have presented your findings.




What are common precipitants of decompensated liver disease?

• Infection
• Increased alcohol intake
• GI bleed
• Underlying malignancy
• Constipation
• Dehydration or increased salt intake
• Hepatotoxic drugs

What are the complications of CLD?

• Portal hypertension and varices which can cause severe GI haemorrhage
• Ascites
• Jaundice
• Encephalopathy
• Spontaneous bacterial peritonitis
• Hepatorenal syndrome
• Hepatopulmonary syndrome
• Hepatocellular carcinoma

 
What are the commonest causes of palmar erythema?

• Chronic liver disease
• Rheumatoid Arthritis
• Thyrotoxicosis
• Pregnancy
• Polycythaemia

 
What are the abdominal causes of finger clubbing?

• Inflammatory Bowel Disease
• Cirrhosis
• Coeliac disease
• Hepatocellular Carcinoma

Autoimmune hepatitis
Autoimmune hepatitis is condition of unknown aetiology which is most commonly seen in young females. Recognised associations include other autoimmune disorders, hypergammaglobulinaemia and HLA B8, DR3. Three types of autoimmune hepatitis have been characterised according to the types of circulating antibodies present

Type IType IIType IIIAnti-nuclear antibodies (ANA) and/or anti-smooth muscle antibodies (SMA)

Affects both adults and children
Anti-liver/kidney microsomal type 1 antibodies (LKM1)

Affects children only
Soluble liver-kidney antigen

Affects adults in middle-age
Features

• may present with signs of chronic liver disease
• acute hepatitis: fever, jaundice etc (only 25% present in this way)
• amenorrhoea (common)
• ANA/SMA/LKM1 antibodies, raised IgG levels
• liver biopsy: inflammation extending beyond limiting plate 'piecemeal necrosis', bridging necrosis

Management

• steroids, other immunosuppressants e.g. azathioprine
• liver transplantation

​Primary biliary cholangitis
Primary biliary cholangitis (previously referred to as primary biliary cirrhosis) is a chronic liver disorder typically seen in middle-aged females (female:male ratio of 9:1). The aetiology is not fully understood although it is thought to be an autoimmune condition. Interlobular bile ducts become damaged by a chronic inflammatory process causing progressive cholestasis which may eventually progress to cirrhosis. The classic presentation is itching in a middle-aged woman

Associations

• Sjogren's syndrome (seen in up to 80% of patients)
• rheumatoid arthritis
• systemic sclerosis
• thyroid disease

Clinical features

• early: may be asymptomatic (e.g. raised ALP on routine LFTs) or fatigue, pruritus
• cholestatic jaundice
• hyperpigmentation, especially over pressure points
• around 10% of patients have right upper quadrant pain
• xanthelasmas, xanthomata
• also: clubbing, hepatosplenomegaly
• late: may progress to liver failure

Diagnosis

• immunology
  • anti-mitochondrial antibodies (AMA) M2 subtype are present in 98% of patients and are highly specific
  • smooth muscle antibodies in 30% of patients
  • raised serum IgM
• imaging
  • required before diagnosis to exclude an extrahepatic biliary obstruction (typically a right upper quadrant ultrasound or magnetic resonance cholangiopancreatography (MRCP)

Management

• first-line: ursodeoxycholic acid
  • slows disease progression and improves symptoms
• pruritus: cholestyramine
• fat-soluble vitamin supplementation
• liver transplantation
  • e.g. if bilirubin > 100 (PBC is a major indication)
  • recurrence in graft can occur but is not usually a problem

Complications

• cirrhosis → portal hypertension → ascites, variceal haemorrhage
• osteomalacia and osteoporosis
• significantly increased risk of hepatocellular carcinoma (20-fold increased risk)

Q

​Haemochromatosis: features
Haemochromatosis is an autosomal recessive disorder of iron absorption and metabolism resulting in iron accumulation. It is caused by inheritance of mutations in the HFE gene on both copies of chromosome 6*. It is often asymptomatic in early disease and initial symptoms often non-specific e.g. lethargy and arthralgia

Epidemiology

• 1 in 10 people of European descent carry a mutation in the genes affecting iron metabolism, mainly HFE
• prevalence in people of European descent = 1 in 200, making it more common than cystic fibrosis

Presenting features

• early symptoms include fatigue, erectile dysfunction and arthralgia (often of the hands)
• 'bronze' skin pigmentation
• diabetes mellitus
• liver: stigmata of chronic liver disease, hepatomegaly, cirrhosis, hepatocellular deposition)
• cardiac failure (2nd to dilated cardiomyopathy)
• hypogonadism (2nd to cirrhosis and pituitary dysfunction - hypogonadotrophic hypogonadism)
• arthritis (especially of the hands)

Questions have previously been asked regarding which features are reversible with treatment:

Reversible complicationsIrreversible complications

• Cardiomyopathy
• Skin pigmentation

• Liver cirrhosis**
• Diabetes mellitus
• Hypogonadotrophic hypogonadism
• Arthropathy

*there are rare cases of families with classic features of genetic haemochromatosis but no mutation in the HFE gene
**whilst elevated liver function tests and hepatomegaly may be reversible, cirrhosis is not
Q

​Hepatitis B
Hepatitis B is a double-stranded DNA hepadnavirus and is spread through exposure to infected blood or body fluids, including vertical transmission from mother to child. The incubation period is 6-20 weeks.

The features of hepatitis B include fever, jaundice and elevated liver transaminases.

Complications of hepatitis B infection

• chronic hepatitis (5-10%). 'Ground-glass' hepatocytes may be seen on light microscopy
• fulminant liver failure (1%)
• hepatocellular carcinoma
• glomerulonephritis
• polyarteritis nodosa
• cryoglobulinaemia

Immunisation against hepatitis B (please see the Greenbook link for more details)

• children born in the UK are now vaccinated as part of the routine immunisation schedule. This is given at 2, 3 and 4 months of age
• at risk groups who should be vaccinated include: healthcare workers, intravenous drug users, sex workers, close family contacts of an individual with hepatitis B, individuals receiving blood transfusions regularly, chronic kidney disease patients who may soon require renal replacement therapy, prisoners, chronic liver disease patients
• contains HBsAg adsorbed onto aluminium hydroxide adjuvant and is prepared from yeast cells using recombinant DNA technology
• around 10-15% of adults fail to respond or respond poorly to 3 doses of the vaccine. Risk factors include age over 40 years, obesity, smoking, alcohol excess and immunosuppression
• testing for anti-HBs is only recommended for those at risk of occupational exposure (i.e. Healthcare workers) and patients with chronic kidney disease. In these patients anti-HBs levels should be checked 1-4 months after primary immunisation
• the table below shows how to interpret anti-HBs levels:

Anti-HBs level (mIU/ml)Response> 100Indicates adequate response, no further testing required. Should still receive booster at 5 years
10 - 100Suboptimal response - one additional vaccine dose should be given. If immunocompetent no further testing is required
< 10Non-responder. Test for current or past infection. Give further vaccine course (i.e. 3 doses again) with testing following. If still fails to respond then HBIG would be required for protection if exposed to the virus


Management of hepatitis B

• pegylated interferon-alpha used to be the only treatment available. It reduces viral replication in up to 30% of chronic carriers. A better response is predicted by being female, < 50 years old, low HBV DNA levels, non-Asian, HIV negative, high degree of inflammation on liver biopsy
• whilst NICE still advocate the use of pegylated interferon firstl-line other antiviral medications are increasingly used with an aim to suppress viral replication (not in a dissimilar way to treating HIV patients)
• examples include tenofovir, entecavir and telbivudine (a synthetic thymidine nucleoside analogue)

Q

Hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the third most common cause of cancer worldwide. Chronic hepatitis B is the most common cause of HCC worldwide with chronic hepatitis C being the most common cause in Europe.

The main risk factor for developing HCC is liver cirrhosis, for example secondary* to hepatitis B & C, alcohol, haemochromatosis and primary biliary cirrhosis. Other risk factors include:

• alpha-1 antitrypsin deficiency
• hereditary tyrosinosis
• glycogen storage disease
• aflatoxin
• drugs: oral contraceptive pill, anabolic steroids
• porphyria cutanea tarda
• male sex
• diabetes mellitus, metabolic syndrome

Features

• tends to present late
• features of liver cirrhosis or failure may be seen: jaundice, ascites, RUQ pain, hepatomegaly, pruritus, splenomegaly
• possible presentation is decompensation in a patient with chronic liver disease
• raised AFP

Screening with ultrasound (+/- alpha-fetoprotein) should be considered for high risk groups such as:

• patients liver cirrhosis secondary to hepatitis B & C or haemochromatosis
• men with liver cirrhosis secondary to alcohol

Management options

• early disease: surgical resection
• liver transplantation
• radiofrequency ablation
• transarterial chemoembolisation
• sorafenib: a multikinase inhibitor

*Wilson's disease is an exception
Q

​Acute upper gastrointestinal bleeding
Acute upper gastrointestinal (GI) bleeding is a common and important presentation. It may be caused by a wide variety of conditions but is most commonly due to either oesophageal varices or peptic ulcer disease.

Clinical features

• haematemesis
  • the most common presenting feature
  • often bright red but may sometimes be described as 'coffee ground'
• melena
  • the passage of altered blood per rectum
  • typically black and 'tarry'
• a raised urea may be seen due to the 'protein meal' of the blood
• features associated with a particular diagnosis e,g,
  • oesophageal varices: stigmata of chronic liver disease
  • peptic ulcer disease: abdominal pain

Differential diagnosis
Oesophageal causes
CausePresenting featuresOesophageal varicesUsually a large volume of fresh blood. Swallowed blood may cause melena. Often associated with haemodynamic compromise. May stop spontaneously but re-bleeds are common until appropriately managed.
OesophagitisSmall volume of fresh blood, often streaking vomit. Melena rare. Often ceases spontaneously. Usually history of antecedent GORD-type symptoms.
CancerUsually small volume of blood, except as a preterminal event with erosion of major vessels. Often associated symptoms of dysphagia and constitutional symptoms such as weight loss. May be recurrent until malignancy is managed.
Mallory Weiss tearTypically brisk small to moderate volume of bright red blood following a bout of repeated vomiting. Melena is rare. Usually ceases spontaneously.
Gastric causes
CausePresenting featuresGastric ulcerSmall low low-volume bleeds are more common so would tend to present as iron deficiency anaemia. Erosion into a significant vessel may produce considerable haemorrhage and haematemesis.
Gastric cancerMay be frank haematemesis or altered blood mixed with vomit. Usually prodromal features of dyspepsia and may have constitutional symptoms. Amount of bleeding variable but erosion of major vessel may produce considerable haemorrhage.
Dieulafoy lesionOften no prodromal features prior to haematemesis and melena, but this arteriovenous malformation may produce quite a considerable haemorrhage and may be difficult to detect endoscopically
Diffuse erosive gastritisUsually haematemesis and epigastric discomfort. Usually, there is an underlying cause such as recent NSAID usage. Large volume haemorrhage may occur with considerable haemodynamic compromise
Duodenual causes
CausePresenting featuresDuodenal ulcerThese are usually posteriorly sited and may erode the gastroduodenal artery. However, ulcers at any site in the duodenum may present with haematemesis, melena and epigastric discomfort.

The pain of a duodenal ulcer is slightly different to that of gastric ulcers and often occurs several hours after eating. Periampullary tumours may bleed but these are rare.
Aorto-enteric fistulaIn patients with previous abdominal aortic aneurysm surgery aorto-enteric fistulation remains a rare but important cause of major haemorrhage associated with high mortality.

Management
NICE published guidelines in 2012 on the management of acute upper gastrointestinal bleeding which is most commonly due to either peptic ulcer disease or oesophageal varices. Some of the key points are detailed below.

Risk assessment

• the Glasgow-Blatchford score at first assessment
  • helps clinicians decide whether patients can be managed as outpatients or not
• the Rockall score is used after endoscopy
  • provides a percentage risk of rebleeding and mortality
  • includes age, features of shock, co-morbidities, aetiology of bleeding and endoscopic stigmata of recent haemorrhage

Blatchford score
Admission risk markerScoreUrea (mmol/L)

(High urea levels in upper GI bleeds are due to the 'protein meal' of blood)6·5 - 8 = 2
8 - 10 = 3
10 - 25 = 4
> 25 = 6
Haemoglobin (g/L)Men

• 12 - 13 = 1
• 10 - 12 = 3
• < 10 = 6

Women

• 10 - 12 = 1
• < 10 = 6

Systolic blood pressure (mmHg)100 - 109 = 1
90 - 99 = 2
< 90 = 3
Other markersPulse >=100/min = 1
Presentation with melaena = 1
Presentation with syncope = 2
Hepatic disease = 2
Cardiac failure = 2
Patients with a Blatchford score of 0 may be considered for early discharge.

Resuscitation

• ABC, wide-bore intravenous access * 2
• platelet transfusion if actively bleeding platelet count of less than 50 x 10*9/litre
• fresh frozen plasma to patients who have either a fibrinogen level of less than 1 g/litre, or a prothrombin time (international normalised ratio) or activated partial thromboplastin time greater than 1.5 times normal
• prothrombin complex concentrate to patients who are taking warfarin and actively bleeding

Endoscopy

• should be offered immediately after resuscitation in patients with a severe bleed
• all patients should have endoscopy within 24 hours

Management of non-variceal bleeding

• NICE do not recommend the use of proton pump inhibitors (PPIs) before endoscopy to patients with suspected variceal upper gastrointestinal bleeding although PPIs should be given to patients with non-variceal upper gastrointestinal bleeding and stigmata of recent haemorrhage shown at endoscopy
• if further bleeding then options include repeat endoscopy, interventional radiology and surgery

Management of variceal bleeding

• terlipressin and prophylactic antibiotics should be given to patients at presentation (i.e. before endoscopy)
• band ligation should be used for oesophageal varices and injections of N-butyl-2-cyanoacrylate for patients with gastric varices
• transjugular intrahepatic portosystemic shunts (TIPS) should be offered if bleeding from varices is not controlled with the above measures

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